No approved therapy exists for cancer-associated cachexia. The colon-26 mouse model of cancer cachexia mimics recent late-stage clinical failures of anabolic anti-cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx-024. The histone deacetylase inhibitor (HDACi) AR-42 exhibited anti-cachectic activity in this model. We explored combined SARM/AR-42 therapy as an improved anti-cachectic treatment paradigm. A reduced dose of AR-42 provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx-024-mediated β-catenin target gene regulation was apparent in cachectic mice only when combined with AR-42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.

中文翻译：

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使用 HDAC 抑制剂克服实验性癌症恶病质中对合成代谢 SARM 疗法的耐药性。

目前还没有批准的治疗癌症相关恶病质的疗法。癌症恶病质的结肠 26 小鼠模型模仿了最近合成代谢抗恶病质治疗的晚期临床失败，并且对多种雄激素的合成代谢剂量无反应，包括选择性雄激素受体调节剂 (SARM) GTx-024。组蛋白脱乙酰酶抑制剂 (HDACi) AR-42 在此模型中表现出抗恶病质活性。我们探索了 SARM/AR-42 联合疗法作为改进的抗恶病质治疗范例。减少剂量的 AR-42 提供有限的抗恶病质功效，但与 GTx-024 联合使用，与对照组相比，显着改善了体重、后肢肌肉质量和握力。AR-42 抑制肌肉中的 IL-6/GP130/STAT3 信号轴，而不影响循环细胞因子。仅当与 AR-42 联合使用时，GTx-024 介导的 β-连环蛋白靶基因调节在恶病质小鼠中才明显。我们的数据表明，该模型中的恶病信号传导涉及对合成代谢 GTx-024 治疗不敏感的分解代谢信号传导以及 GTx-024 介导的合成代谢信号传导的阻断。AR-42 减轻分解代谢基因激活并恢复对 GTx-024 的合成代谢反应。将 GTx-024（一种临床建立的合成代谢疗法）与 AR-42（一种经过临床评估的 HDACi）相结合，代表了一种改善恶病质患者合成代谢反应的有前途的方法。